Placebo-controlled Parallel Group Study Research Articles

Effect of benralizumab on inflammation in skin after intradermal allergen challenge in patients with moderate-to-severe atopic dermatitis

BackgroundAtopic dermatitis is a skin barrier dysfunction characterized by tissue eosinophilia. Objective: In patients with atopic dermatitis (AD) we evaluated the effect of eosinophil depletion with benralizumab on markers of inflammation in skin after intradermal allergen challenge. Methods20 patients with moderate to severe AD completed a randomized, double-blind, placebo-controlled parallel-group study comparing 3 doses q4wk 30 mg subcutaneous benralizumab (n=9) to placebo (n=11). Allergen and saline control intradermal challenges were conducted before and after treatment with skin biopsies collected 24 hours after challenge. Early (ECR) and late cutaneous responses (LAR) were measured by skin wheal size. Eosinophils and IL-5Rα -bearing cells including eosinophil progenitor cells (EoP), basophils and mast cells were measured in papillary dermis by immunofluorescence microscopy, and EoP, hemopoietic progenitor cells (HPC) and ILC2 were measured in blood by flow cytometry. Outcomes were compared between placebo and benralizumab treatment groups using Mann-Whitney U-test. ResultsBenralizumab reduced eosinophils in blood (p<0.0001), and allergen challenged skin as measured by H&E and EG2 (p<0.05). Benralizumab lowered levels of EoP, mast cells and basophil numbers in skin, as well as EoP, HPC and ILC2s in blood (all p<0.05). There was a trend for improvement in the ECR response (p=0.095), but no effect on the LCR. ConclusionIn patients with moderate to severe AD, benralizumab treatment significantly inhibited accumulation of eosinophils and other IL-5Rα expressing cells in the papillary dermis after intradermal allergen challenge. Targeting IL-5Rα positive cells did not modulate the size of the allergen-induced skin wheal. (ClincialTrials.gov number, NCT03563066).

Corticosteroids for preventing postherpetic neuralgia.

Postherpetic neuralgia (PHN) is a common, serious, painful complication of herpes zoster. Corticosteroids have anti-inflammatory properties, and might be beneficial. This is an update of a review first published in 2008, and previously updated in 2013. To assess the effects (benefits and harms) of corticosteroids in preventing postherpetic neuralgia. We updated the searches for randomised controlled trials (RCTs) of corticosteroids for preventing postherpetic neuralgia in the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, two other databases, and two trials registers (June 2022). We also reviewed the bibliographies of identified trials, contacted authors, and approached pharmaceutical companies to identify additional published or unpublished data. We included all RCTs involving corticosteroids given by oral, intramuscular, or intravenous routes for people of all ages, with herpes zoster of all degrees of severity within seven days after onset, compared with no treatment or placebo, but not with other treatments. Two review authors independently identified potential articles, extracted data, assessed the risk of bias of each trial, and the certainty of the evidence. Disagreement was resolved by discussion among the co-authors. We followed standard Cochrane methodology. We identified five trials with a total of 787 participants that met our inclusion criteria. No new studies were identified for this update. All were randomised, double-blind, placebo-controlled parallel-group studies. The evidence is very uncertain about the effects of corticosteroids given orally during an acute herpes zoster infection in preventing postherpetic neuralgia six months after the onset of herpes (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.45 to 1.99; 2 trials, 114 participants; very low-certainty evidence (downgraded for serious risk of bias and very serious imprecision)). The three other trials that fulfilled our inclusion criteria were not included in the meta-analysis because they did not provide separate information on the number of participants with PHN at six months. Adverse events during or within two weeks after stopping treatment were reported in all five included trials. There were no observed differences in serious (RR 1.65, 95% CI 0.51 to 5.29; 5 trials, 755 participants; very low-certainty evidence (downgraded for serious risk of bias and very serious imprecision)), or non-serious adverse events (RR 1.30, 95% CI 0.90 to 1.87; 5 trials, 755 participants; low-certainty evidence (downgraded for serious risk of bias and serious imprecision)) between the corticosteroid and placebo groups. One of these trials was at high risk of bias because of incomplete outcome data, two were at unclear risk of bias, and the other was at low risk of bias. The review was first published in 2008; no new RCTs were identified for inclusion in subsequent updates in 2010, 2013, and 2023. Based on the current available evidence, we are uncertain about the effects of corticosteroids given orally during an acute herpes zoster infection on preventing postherpetic neuralgia. Corticosteroids given orally or intramuscularly may result in little to no difference in the risk of adverse events in people with acute herpes zoster. Some researchers have recommended using corticosteroids to relieve the zoster-associated pain in the acute phase of the disease. If further research is designed to evaluate the efficacy of corticosteroids for herpes zoster, long-term follow-up should be included to observe their effect on the transition from acute pain to postherpetic neuralgia. Future trials should include measurements of function and quality of life, as well as updated measures of pain.

Efficacy and safety of ligelizumab in adults and adolescents with chronic spontaneous urticaria: results of two phase 3 randomised controlled trials

Many patients with chronic spontaneous urticaria (CSU) do not achieve complete control of their symptoms with current available treatments. In a dose-finding phase 2b study, ligelizumab improved urticaria symptoms in patients with H1-antihistamine (H1-AH) refractory CSU. Here, we report the efficacy and safety outcomes from two ligelizumab phase 3 studies. PEARL-1 and PEARL-2 were identically designed randomised, double-blind, active-controlled and placebo-controlled parallel-group studies. Patients aged 12 years or older with moderate-to-severe H1-AH refractory CSU were recruited from 347 sites in 46 countries and randomly allocated in a 3:3:3:1 ratio via Interactive Response Technology to 72 mg ligelizumab, 120 mg ligelizumab, 300 mg omalizumab, or placebo, dosed every 4 weeks, for 52 weeks. Patients allocated to placebo received 120 mg ligelizumab from week 24. The primary endpoint was change-from-baseline (CFB) in weekly Urticaria Activity Score (UAS7) at week 12, and was analysed in all eligible adult patients according to the treatment assigned at random allocation. Safety was assessed throughout the study in all patients who received at least one dose of the study drug. The studies were registered with ClinicalTrials.gov, NCT03580369 (PEARL-1) and NCT03580356 (PEARL-2). Both trials are now complete. Between Oct 17, 2018, and Oct 26, 2021, 2057 adult patients were randomly allocated across both studies (72 mg ligelizumab n=614; 120 mg ligelizumab n=616; 300 mg omalizumab n=618, and placebo n=209). A total of 1480 (72%) of 2057 were female, and 577 (28%) of 2057 were male. Mean UAS7 at baseline across study groups ranged from 29·37 to 31·10. At week 12, estimated treatment differences in mean CFB-UAS7 were as follows: for 72 mg ligelizumab versus placebo, -8·0 (95% CI -10·6 to -5·4; PEARL-1), -10·0 (-12·6 to -7·4; PEARL-2); 72 mg ligelizumab versus omalizumab 0·7 (-1·2 to 2·5; PEARL-1), 0·4 (-1·4 to 2·2; PEARL-2); 120 mg ligelizumab versus placebo -8·0 (-10·5 to -5·4; PEARL-1), -11·1 (-13·7 to -8·5; PEARL-2); 120 mg ligelizumab versus omalizumab 0·7 (-1·1 to 2·5; PEARL-1), -0·7 (-2·5 to 1·1; PEARL-2). Both doses of ligelizumab were superior to placebo (p<0·0001), but not to omalizumab, in both studies. No new safety signals were identified for ligelizumab or omalizumab. In the phase 3 PEARL studies, ligelizumab demonstrated superior efficacy versus placebo but not versus omalizumab. The safety profile of ligelizumab was consistent with previous studies. Novartis Pharma.

Ferric derisomaltose and Outcomes in the Recovery of Gynecologic oncology: ERAS (Enhanced Recovery After Surgery) (FORGE) – a protocol for a pilot randomised double-blinded parallel-group placebo-controlled study of the feasibility and efficacy of intravenous ferric derisomaltose to correct preoperative iron-deficiency anaemia in patients undergoing gynaecological oncology surgery

IntroductionIron-deficiency anaemia is common in gynaecological oncology patients. Blood transfusions are immunosuppressive and carry immediate and long-term risks. Oral iron replacement remains the standard of care but requires prolonged treatment...

Randomized, double-blind, placebo-controlled study to evaluate the effect of treatment with an SPMs-enriched oil on chronic pain and inflammation, functionality, and quality of life in patients with symptomatic knee osteoarthritis: GAUDI study

BackgroundSpecialized pro-resolving mediators (SPMs), including 18-HEPE, 17-HDHA, and 14-HDHA are recognized as potentially therapeutic in inflammatory diseases because SPMs regulate the inflammation process, which leads to, for example; swelling and the sensation of pain. In osteoarthritis (OA), chronic pain is described as the symptom that reduces patients´ quality of life (QoL). The GAUDI study evaluated the efficacy of SPMs supplementation in reducing pain in the symptomatic knee of OA patients.MethodsThis randomized, multicenter, double-blind, and placebo-controlled parallel-group pilot study was performed in Spain and conducted on adults 18–68 years old diagnosed with symptomatic knee OA. Patients were enrolled in the study for up to 24 weeks, which included a 12-week intervention period and a follow-up visit on week 24. The primary endpoint was pain change measured through a Visual Analog Scale (VAS). Secondary endpoints included: Pain change evaluation, stiffness, and function according to the WOMAC index; assessment of constant, intermittent, and total pain according to the OMERACT-OARSI score; evaluation of changes in health-related QoL parameters; the use or not of concomitant, rescue, and anti-inflammatory medication; and safety and tolerability assessments.ResultsPatients were enrolled in the study from May 2018 to September 2021. VAS pain score was evaluated in the per protocol population (n = 51 patients), in which we observed a statistically significant reduction after 8 weeks (p = 0.039) and 12 weeks (p = 0.031) of treatment in patients consuming SPMs (n = 23 subjects) vs. placebo (n = 28 subjects). In line with the OMERACT-OARSI score, intermittent pain was reduced after 12 weeks with statistical significance (p = 0.019) in patients treated with SPMs (n = 23 subjects) vs. placebo (n = 28 subjects). Functional status as WOMAC score did not significantly change after SPMs or placebo consumption. Notably, patients consuming SPMs showed improvements in all five aspects of the EUROQoL-5, including a significant improvement in the usual-activities dimension. None of the patients required rescue medication, nor were any adverse events reported.ConclusionsThese findings suggest that sustained SPMs consumption reduces pain in OA patients while also improving their Quality of Life. These results also support the safety profile of SPMs supplementation.Trial registration NCT05633849. Registered 1 December 1 2022. Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT05633849

Effects of egg yolk choline intake on cognitive functions and plasma choline levels in healthy middle-aged and older Japanese: a randomized double-blinded placebo-controlled parallel-group study

BackgroundCholine, as a neurotransmitter acetylcholine precursor, is reportedly associated with cognitive function. Although there are several cohort and animal studies on choline-containing foods and cognitive function, only a few interventional studies were reported. Egg yolk is a rich source of different choline-containing chemical forms, such as phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and α-glycerophosphocholine (α-GPC). This study aimed to investigate the effect of consuming 300 mg of egg yolk choline per day on cognitive function of Japanese adults.MethodsA 12-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted in 41 middle-aged and elderly males and females (43.9% female) aged ≥ 60 years and ≤ 80 years without dementia. Participants were randomly assigned to placebo and choline groups. The choline group received a supplement containing egg yolk choline (300 mg/day), and the placebo group received an egg yolk supplement free from choline for 12 weeks. Assessments of Cognitrax, Trail Making Tests (TMT) part A and B, the MOS 36-Item Short-Form Health Survey (SF-36), the Simplified Japanese Version of the WHO-Five Well-Being Index (WHO-5), and plasma choline levels were performed before and 6 and 12 weeks after supplement intake. In the present study, 19 subjects (9 in the placebo group and 10 in the choline group) were excluded due to the violation of the discontinuation criteria or participant compliance, and 41 subjects were analyzed.ResultsThe change amount of verbal memory scores and verbal memory test-correct hit (delay) was significantly higher in the choline group than in the placebo group at baseline-6 and baseline-12 weeks. The plasma free choline level was significantly higher in the choline group compared with the placebo group at 6 weeks. Conversely, the choline group showed significantly lower Cognitrax processing speed scores, symbol digit coding testing correct responses, and SF-36 physical quality of life summary scores compared to the placebo group at 6 weeks.ConclusionsThe results suggested that continued 300 mg/day intake of egg yolk choline improved verbal memory, which is a part of cognitive functions. To confirm the observed effects of egg yolk choline, more well-designed and large-scale studies are warranted.Trial registrationStudy protocols were pre-registered in the Clinical Trials Registration System (UMIN-CTR) (UMIN 000045050).

No effect of the turmeric root phenol curcumin on prednisolone-induced glucometabolic perturbations in men with overweight or obesity.

Preclinically, curcumin has been shown to protect against glucocorticoid-induced insulin resistance. We evaluated the effect of curcumin administered with prednisolone in healthy overweight or obese men. In a double-blind, parallel-group trial, 24 overweight/obese non-diabetic men were randomised to one of three intervention groups (A) prednisolone placebo+curcumin placebo, (B) prednisolone (50 mg/day)+curcumin placebo or (C) prednisolone and curcumin (400 mg/day). Curcumin or curcumin placebo treatment started 1 day prior to 10-day prednisolone or prednisolone placebo treatment. The primary endpoint was change in prednisolone-induced insulin resistance assessed by homeostatic model assessment of insulin resistance (HOMA2-IR). Other endpoints included anthropometric measurements, magnetic resonance spectroscopy-assessed hepatic fat content, blood pressure, circulating metabolic markers and continuous glucose monitoring measures. Baseline characteristics (mean ± s.d): age 44.2 ± 13.7 years, BMI 30.1 ± 3.5 kg/m2, HbAlc 33.3 ± 3.2 mmol/mol, HOMA2-IR 1.10 ± 0.45 and fasting plasma glucose 5.2 ± 0.4 mmol/L. Prednisolone significantly increased HOMA2-IR (estimated treatment difference 0.36 (95% CI 0.16; 0.57)). Co-treatment with curcumin had no effect on HOMA2-IR (estimated treatment difference 0.08 (95% CI -0.13; 0.39)). Prednisolone increased HbAlc, insulin, C-peptide, glucagon, blood pressure, mean interstitial glucose, time spent in hyperglycaemia and glucose variability, but no protective effect of curcumin on any of these measures was observed. In this double-blind, placebo-controlled parallel-group study involving 24 overweight or obese men randomised to one of three treatment arms, curcumin treatment had no protective effect on prednisolone-induced insulin resistance or other glucometabolic perturbations.

Intake of Lactobacillus paragasseri SBT2055 improves subjective symptoms of common cold during winter season in healthy adults: A randomized, double-blind, placebo-controlled parallel-group comparative study.

Lactobacillus paragasseri SBT2055 (LG2055) has been reported to show immunostimulating effects. This study aimed to investigate the effects of LG2055 on the subjective symptoms of the physical condition in healthy adults. In this randomized, double-blind, placebo-controlled, parallel-group comparative study, Japanese individuals aged 20-64 years were recruited. A total of 200 participants were randomly divided into two groups by an independent controller (LG2055 and placebo groups; 100 participants per group). Drinkable yogurts containing LG2055 or lacking LG2055 (placebo) were used as test samples. The participants ingested one bottle of the test sample once a day for 12 weeks. A daily physical health questionnaire survey (about common cold symptoms) was performed as the primary outcome, and immunological and oxidative stress markers in saliva and serum were evaluated as secondary outcomes. In total, 198 participants completed the scheduled intake of the test samples, and five participants were excluded from the final analysis. Consequently, 193 participants (LG2055 group, n = 97; placebo group, n = 96) in the Per-Protocol Set were included in the efficacy analysis. The cumulative days of each symptom were evaluated, and the LG2055 group showed a significantly higher ratio of "without symptom" in runny nose, plugged nose, sneezing, sore throat, hoarseness, cough, headache, feeling tired, and fever than the placebo group, indicating that the incidence rates of common cold symptoms were lower in the LG2055 group. Additionally, changes in the salivary secretory IgA levels were significantly higher, and the serum derivatives of reactive oxygen metabolites levels were significantly lower in the LG2055 group. Our study revealed that intake of LG2055 decreased common cold symptoms and improved immune parameters in healthy adults. This suggests that LG2055 contributes to the maintenance of physical conditions by improving the host immune system. [https://www.umin.ac.jp/ctr/index.htm], identifier [UMIN000045901].

Prospective multicentre randomized double-blind placebo-controlled parallel group study on the efficacy and tolerability of StroVac® in patients with recurrent symptomatic uncomplicated bacterial urinary tract infections

PurposeTo evaluate efficacy and safety of vaccination with StroVac compared to placebo in patients with recurrent urinary tract infections (rUTI).Material and methodsWe performed a prospective, double-blinded, placebo-controlled study in patients with uncomplicated rUTI. Patients received three single intramuscular injections with StroVac every two weeks. Primary endpoint was the number of bacterial urinary tract infections (UTI) over 13.5 months after randomization and adjusted by the respective “baseline” value when comparing verum and placebo group. Secondary endpoints were the number of patients with non-recurrence, time to first recurrence, frequency of recurrences, and patients' self-assessment of quality of life using a validated questionnaire.Results376 patients were randomized to both groups between January 2012 and March 2015. Mean age was 44.4 years. Patients were mainly female (98.4%). In the StroVac group (n = 188), the number of UTIs was reduced from 5.5 to 1.2, in the placebo group (n = 188) from 5.4 to 1.3 (p = 0.63). In patients with ≥ 7 UTIs prior to study inclusion, StroVac was statistically significantly superior to placebo (p = 0.048). However, in all other secondary endpoints, no statistical differences between the two groups could be seen (all p > 0.3).ConclusionStroVac reduced the number of clinically relevant UTIs like in former studies but did not show statistically significant better results than the chosen placebo. Most likely, that was due to a, since confirmed, prophylactic effect of the chosen placebo itself. Therefore, placebo-controlled and double-blinded studies using a different ineffective placebo preparation are needed to determine the importance of StroVac in prophylaxis of rUTI.

Efficacy and Safety of TurmXTRA® 60N in Delayed Onset Muscle Soreness in Healthy, Recreationally Active Subjects: A Randomized, Double-Blind, Placebo-Controlled Trial.

Background Delayed onset of muscle soreness (DOMS) and its physiological consequences influenced an individual's adherence to an exercise routine. Objective This study aimed to evaluate the efficacy, safety, and tolerability of TurmXTRA® 60N (WDTE60N) on DOMS compared to placebo in recreationally active healthy subjects. Methods This randomized, double-blind, placebo-controlled parallel-group study enrolled 30 healthy and recreationally active subjects (average age: 28.23 ± 4.20 years) and randomized them to receive WDTE60N (WDTE60N group; n = 15) or placebo (placebo group; n = 15). Study treatments were initiated 29 days before the eccentric exercise and were continued for 4 days after the exercise. The primary endpoint was the change in pain intensity measured by the visual analog scale (VAS) at the end of study treatment (at 96 hours after eccentric exercise) from baseline (measured immediately after exercise). Results The VAS score indicated that subjects from the WDTE60N group reported significantly less pain after eccentric exercise compared to the placebo group (AUC0–96h: 286.8 ± 46.7 vs. 460 ± 40.5, respectively; p < 0.0001). Well-being status was assessed using the adapted version of the Hooper and MacKinnon questionnaire and was calculated as individual and cumulative scores of the domains (fatigue, mood, general muscle soreness, sleep quality, and stress) that demonstrated improvement in all domains and in overall well-being in the WDTE60N group compared to the placebo group (p < 0.0001). Serum lactate dehydrogenase (LDH) was significantly lower in the WDTE60N group compared to the placebo group (AUC0–96h: 23623.7 ± 2532.0 vs. 26138.6 ± 3669.5, respectively; p=0.0446). Conclusion Intake of WDTE60N before and after eccentric exercise significantly reduced subjective perception of muscle soreness and serum LDH activity and increased the psychological well-being in recreationally active subjects.

Acetylcysteine has No Mechanistic Effect in Patients at Risk of Contrast-Induced Nephropathy: A Failure of Academic Clinical Science.

Contrast‐induced nephropathy (CIN) is a major complication of imaging in patients with chronic kidney disease (CKD). The publication of an academic randomized controlled trial (RCT; n = 83) reporting oral (N)‐acetylcysteine (NAC) to reduce CIN led to > 70 clinical trials, 23 systematic reviews, and 2 large RCTs showing no benefit. However, no mechanistic studies were conducted to determine how NAC might work; proposed mechanisms included renal artery vasodilatation and antioxidant boosting. We evaluated the proposed mechanisms of NAC action in participants with healthy and diseased kidneys. Four substudies were performed. Two randomized, double‐blind, placebo‐controlled, three‐period crossover studies (n = 8) assessed the effect of oral and intravenous (i.v.) NAC in healthy kidneys in the presence/absence of iso‐osmolar contrast (iodixanol). A third crossover study in patients with CKD stage III (CKD3) (n = 8) assessed the effect of oral and i.v. NAC without contrast. A three‐arm randomized, double‐blind, placebo‐controlled parallel‐group study, recruiting patients with CKD3 (n = 66) undergoing coronary angiography, assessed the effect of oral and i.v. NAC in the presence of contrast. We recorded systemic (blood pressure and heart rate) and renal (renal blood flow (RBF) and glomerular filtration rate (GFR)) hemodynamics, and antioxidant status, plus biomarkers of renal injury in patients with CKD3 undergoing angiography. Primary outcome for all studies was RBF over 8 hours after the start of i.v. NAC/placebo. NAC at doses used in previous trials of renal prophylaxis was essentially undetectable in plasma after oral administration. In healthy volunteers, i.v. NAC, but not oral NAC, increased blood pressure (mean area under the curve (AUC) mean arterial pressure (MAP): mean difference 29 h⋅mmHg, P = 0.019 vs. placebo), heart rate (28 h⋅bpm, P < 0.001), and RBF (714 h⋅mL/min, 8.0% increase, P = 0.006). Renal vasodilatation also occurred in the presence of contrast (RBF 917 h⋅mL/min, 12% increase, P = 0.005). In patients with CKD3 without contrast, only a rise in heart rate (34 h⋅bpm, P = 0.010) and RBF (288 h⋅mL/min, 6.0% increase, P = 0.001) occurred with i.v. NAC, with no significant effect on blood pressure (MAP rise 26 h⋅mmHg, P = 0.156). Oral NAC showed no effect. In patients with CKD3 receiving contrast, i.v. NAC increased blood pressure (MAP rise 52 h⋅mmHg, P = 0.008) but had no effect on RBF (151 h⋅mL/min, 3.0% increase, P = 0.470), GFR (29 h⋅mL/min/1.73m², P = 0.122), or markers of renal injury. Neither i.v. nor oral NAC affected plasma antioxidant status. We found oral NAC to be poorly absorbed and have no reno‐protective effects. Intravenous, not oral, NAC caused renal artery vasodilatation in healthy volunteers but offered no protection to patients with CKD3 at risk of CIN. These findings emphasize the importance of mechanistic clinical studies before progressing to RCTs for novel interventions. Thousands were recruited to academic clinical trials without the necessary mechanistic studies being performed to confirm the approach had any chance of working.

Short-Term Subcutaneous Allergy Immunotherapy and Dupilumab are Well Tolerated in Allergic Rhinitis: A Randomized Trial.

BackgroundSubcutaneous immunotherapy (SCIT) has been proven as an effective therapy against some allergens for seasonal allergic rhinitis (SAR) patients unresponsive to intranasal corticosteroids and/or antihistamines but carries risk of systemic allergic reactions. Dupilumab blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation in multiple diseases.ObjectiveTo evaluate the efficacy and safety of SCIT+dupilumab vs SCIT alone.MethodsThis phase 2a, multicenter, double-blind, placebo-controlled parallel-group study conducted in 103 adults with grass pollen-induced SAR (NCT03558997) randomized patients 1:1:1:1 to SCIT, dupilumab (300 mg every 2 weeks), SCIT+dupilumab, or placebo. SCIT was administered using an 8-week cluster protocol followed by 8 weeks of maintenance injections. Primary endpoint was change from pre-treatment baseline in area under the curve (AUC) in total nasal symptom score (TNSS) 0–1 h following nasal allergen challenge (NAC) with timothy grass extract at Week 17.ResultsAlthough 16 weeks of treatment with SCIT+dupilumab did not significantly improve TNSS AUC (0–1 h) following NAC at Week 17 vs SCIT (least squares mean −56.76% vs −52.03%), a higher proportion of SCIT+dupilumab-treated patients (61.5%) achieved SCIT maintenance dose vs SCIT (46.2%). A lower proportion of SCIT+dupilumab-treated patients (7.7%) required epinephrine rescue treatment vs SCIT (19.2%). There were significantly fewer withdrawals in the SCIT+dupilumab group than in the SCIT group (n = 2 [7.7%] vs n = 8 [30.8%]; P = 0.0216); the majority of SCIT group withdrawals were due to SCIT-related intolerability, compared with no discontinuations from the SCIT+dupilumab group.ConclusionIn SAR patients, 16 weeks of SCIT+dupilumab may improve SCIT tolerability but did not incrementally reduce post-allergen challenge nasal symptoms compared with SCIT alone.Clinical Study NumberNCT03558997.

Polymethoxyflavone purified fromKaempferia parviflorareduces visceral fat in Japanese overweight individuals: a randomised, double-blind, placebo-controlled study

Visceral fat is a more important factor in obesity-associated disorders in Japanese individuals than in Caucasian individuals. The objective of this randomised, double-blind, placebo-controlled parallel group study, conducted in Japanese overweight adults, was to investigate the effects of polymethoxyflavone purified from Kaempferia parviflora on visceral fat. A total of 80 subjects (aged 20-64 years, 23.0 ≤ body mass index < 30 kg m-2) were randomly assigned in 1 : 1 ratio to either the active (polymethoxyflavone purified from K. parviflora) or placebo group. Over a 12-week period, each subject received two capsules containing polymethoxyflavone purified from K. parviflora (12 mg polymethoxyflavone per day) or placebo. The primary outcome was a reduction in visceral fat area (VFA), while the secondary outcome was a reduction in subcutaneous fat area (SFA) and total fat area (TFA). VFA was measured at 0, 8, and 12 weeks using computed tomography scanning. Results showed that VFA significantly reduced after 12 weeks in the active group and was significantly lower than in the placebo group at 8 and 12 weeks. A significant reduction was observed in SFA and TFA after 8 and 12 weeks in the active group; TFA was significantly lower than that in the placebo group at 8 and 12 weeks. No adverse events associated with the test supplements were observed in either group. Our study shows that administration of polymethoxyflavone purified from K. parviflora reduces visceral fat in Japanese overweight adults.

Low Intensity, Transcranial, Alternating Current Stimulation Reduces Migraine Attack Burden in a Home Application Set-Up: A Double-Blinded, Randomized Feasibility Study.

Background: Low intensity, high-frequency transcranial alternating current stimulation (tACS) applied over the motor cortex decreases the amplitude of motor evoked potentials. This double-blind, placebo-controlled parallel group study aimed to test the efficacy of this method for acute management of migraines. Methods: The patients received either active (0.4 mA, 140 Hz) or sham stimulation for 15 min over the visual cortex with the number of terminated attacks two hours post-stimulation as the primary endpoint, as a home therapy option. They were advised to treat a maximum of five migraine attacks over the course of six weeks. Results: From forty patients, twenty-five completed the study, sixteen in the active and nine in the sham group with a total of 102 treated migraine attacks. The percentage of terminated migraine attacks not requiring acute rescue medication was significantly higher in the active (21.5%) than in the sham group (0%), and the perceived pain after active stimulation was significantly less for 2–4 h post-stimulation than after sham stimulation. Conclusion: tACS over the visual cortex has the potential to terminate migraine attacks. Nevertheless, the high drop-out rate due to compliance problems suggests that this method is impeded by its complexity and time-consuming setup.

A Double-Blind, Placebo-Controlled Parallel Group Study to Evaluate the Effect of a Single Oral Dose of 5-HT1A Antagonist GSK958108 on Ejaculation Latency Time in Male Patients Suffering From Premature Ejaculation

BackgroundPremature ejaculation (PE) is a common male neurobiological sexual disorder, related to a disturbance in central serotonin (5-hydroxytryptamine or 5-HT) neurotransmission. AimTo assess the efficacy of a single oral dose of 5HT1A receptor antagonist GSK958108 on ejaculation latency time (ELT) in male subjects suffering from PE. MethodsA total of 35 male subjects were enrolled in a Phase 1 double-blind, placebo-controlled, parallel group masturbation-model study. All subjects completed the study. No subject was withdrawn from the study. There were no major protocol deviations reported during the study. OutcomesThe primary outcome of the study was to evaluate the effect of a single oral dose of 5HT1A receptor antagonist GSK958108 on ELT as measured in the masturbation model; additionally, we investigated drug’s safety and tolerability. ResultsIn the 3 mg GSK958108 treatment group, the ELT was estimated to be 16% longer (1.542 vs 1.328, 95% CI: -16% to +61%) than if the subjects had taken placebo. In the 7 mg GSK958108 treatment group, the ELT was estimated to be 77% longer (2.346 vs 1.328, 95% CI: +28% to +144%) than in the placebo group. The systemic exposure to GSK958108 increased with dosage between 3 mg and 7 mg. A significant trend toward an increase of ELT was observed with increasing plasma concentrations of GSK958108. A total of 4 patients all treated with 7 mg dose experienced minor drug related adverse events (5 adverse events in 4 patients): somnolence (n = 3), headache (n = 1), tinnitus (n = 1). Clinical ImplicationsIn the current double-blind, placebo-controlled parallel group study the 5HT1A receptor antagonist GSK958108 was tested in 3 mg and 7 mg doses for PE treatment in humans. It was shown that GSK958108 significantly delayed ejaculation showing a new and safe alternative in PE treatment. Strengths & LimitationsThe present study showed innovative results suggesting an important role of 5HT1A receptor antagonist in the PE treatment. However, the use of masturbation model and the small population are the main limitations of this investigation. Conclusion5HT1A receptor antagonist GSK958108 3 mg per day and 7 mg per day was found to be well-tolerated, safe and effective for the treatment of PE subjects and demonstrated a strong association between 5HT1A receptors and ejaculation control in humans (NCT00861484).Migliorini F, Tafuri A, Bettica P, et al. A Double-Blind, Placebo-Controlled Parallel Group Study to Evaluate the Effect of a Single Oral Dose of 5-HT1A Antagonist GSK958108 on Ejaculation Latency Time in Male Patients Suffering From Premature Ejaculation. J Sex Med 2021;18:63–71.

P.326 Efficacy of resveratrol in the treatment of unipolar depression: double-blind randomized placebo-controlled parallel-group study

An enhanced vasoconstrictor activity of cutaneous arteries participates in the reduction of skin blood flow induced by cooling stimulation. Raynaud's phenomenon, which is characterized by intense cooling-induced constriction of cutaneous arteries, is more common in women during the period from menarche to menopause. We thus investigated the effect of 17β-estradiol (E2) on cooling-induced reduction of plantar skin blood flow (PSBF) in mouse in vivo. Ovariectomized female ddY mice, anaesthetized with pentobarbital, were treated with tetrodotoxin for eliminating the sympathetic nerve tone and artificially ventilated. The PSBF was measured by laser Doppler flowmetry. Cooling air temperature around the foot from 25 to 20, 15, or 10 °C decreased the PSBF in a temperature-dependent manner, which was suppressed by the specific α2C-adrenoceptor antagonist MK-912. When E2 was intravenously administered as a bolus followed by a constant infusion for 10 min just before the cooling stimulation, the cooling-induced reduction of PSBF was facilitated by E2 in a dose-dependent manner. The facilitatory effect of E2 was not induced after the treatment with MK-912. Similar facilitatory effect was induced by an intravenous application of G-1, an agonist of G protein-coupled estrogen receptor (GPER, also termed GPR30). Moreover, the facilitatory effect of E2 was abolished by the GPER antagonist G15. These results suggest that acute administration of E2 leads to the facilitation of cooling-induced, α2C-adrenoceptor-mediated reduction of skin blood flow via the activation of the non-genomic estrogen receptor GPER.

Topic Application of the Probiotic Streptococcus dentisani Improves Clinical and Microbiological Parameters Associated With Oral Health.

Streptococcus dentisani 7746, isolated from dental plaque of caries-free individuals, has been shown to have several beneficial effects in vitro which could contribute to promote oral health, including an antimicrobial activity against oral pathogens by the production of bacteriocins and a pH buffering capacity through ammonia production. Previous work has shown that S. dentisani was able to colonize the oral cavity for 2–4 weeks after application. The aim of the present work was to evaluate its clinical efficacy by a randomized, double-blind, placebo-controlled parallel group study. Fifty nine volunteers were enrolled in the study and randomly assigned to a treatment or placebo group. The treatment consisted of a bucco-adhesive gel application (2.5 109 cfu/dose) with a dental splint for 5 min every 48 h, for a period of 1 month (i.e., 14 doses). Dental plaque and saliva samples were collected at baseline, 15 and 30 days after first application, and 15 days after the end of treatment. At baseline, there was a significant correlation between S. dentisani levels and frequency of toothbrushing. Salivary flow, a major factor influencing oral health, was significantly higher in the probiotic group at day 15 compared with the placebo (4.4 and 3.4 ml/5 min, respectively). In the probiotic group, there was a decrease in the amount of dental plaque and in gingival inflammation, but no differences were observed in the placebo group. The probiotic group showed a significant increase in the levels of salivary ammonia and calcium. Finally, Illumina sequencing of plaque samples showed a beneficial shift in bacterial composition at day 30 relative to baseline, with a reduction of several cariogenic organisms and the key players in plaque formation, probably as a result of bacteriocins production. Only 58% of the participants in the probiotic group showed increased plaque levels of S. dentisani at day 30 and 71% by day 45, indicating that the benefits of S. dentisani application could be augmented by improving colonization efficiency. In conclusion, the application of S. dentisani 7746 improved several clinical and microbiological parameters associated with oral health, supporting its use as a probiotic to prevent tooth decay.

Lactobacillus paracasei KW3110 Suppresses Inflammatory Stress-Induced Premature Cellular Senescence of Human Retinal Pigment Epithelium Cells and Reduces Ocular Disorders in Healthy Humans.

Lactobacillus paracasei KW3110 (KW3110) has anti-inflammatory effects and mitigates retinal pigment epithelium (RPE) cell damage caused by blue-light exposure. We investigated whether KW3110 suppresses chronic inflammatory stress-induced RPE cell damage by modulating immune cell activity and whether it improves ocular disorders in healthy humans. First, we showed that KW3110 treatment of mouse macrophages (J774A.1) produced significantly higher levels of interleukin-10 as compared with other lactic acid bacterium strains (all p < 0.01). Transferring supernatant from KW3110- and E. coli 0111:B4 strain and adenosine 5′-triphosphate (LPS/ATP)-stimulated J774A.1 cells to human retinal pigment epithelium (ARPE-19) cells suppressed senescence-associated phenotypes, including proliferation arrest, abnormal appearance, cell cycle arrest, and upregulation of cytokines, and also suppressed expression of tight junction molecule claudin-1. A randomized, double-blind, placebo-controlled parallel-group study of healthy subjects (n = 88; 35 to below 50 years) ingesting placebo or KW3110-containing supplements for 8 weeks showed that changes in critical flicker frequency, an indicator of eye fatigue, from the week-0 value were significantly larger in the KW3110 group at weeks 4 (p = 0.040) and 8 (p = 0.036). These results suggest that KW3110 protects ARPE-19 cells against premature senescence and aberrant expression of tight junction molecules caused by chronic inflammatory stress, and may improve chronic eye disorders including eye fatigue.

PS-5-6 A Double-Blind, Placebo-Controlled Parallel Group Study to Evaluate the Effect of a Single Oral Dose of GSK958108 on Ejaculation Latency Time in Male Patients Suffering From Premature Ejaculation

PS-5-6 A Double-Blind, Placebo-Controlled Parallel Group Study to Evaluate the Effect of a Single Oral Dose of GSK958108 on Ejaculation Latency Time in Male Patients Suffering From Premature Ejaculation

Effect of ellagic acid on body fat and triglyceride reduction in healthy overweight volunteers: a randomized, double-blind, placebo-controlled parallel group study

Background: Worldwide, those categorized as overweight or obese are increasing at an alarming rate, posing a serious public health problem. Current management methods vary, ranging from surgery, dieting and exercise, to the use of synthetic and natural compounds. Previous studies reported the use of an Irvingia gabonensis extract containing ellagic acid in reducing weight and other related parameters in overweight participants. The present study investigated the efficacy of ellagic acid on anthropometric parameters as well as body fat ratio and blood triglyceride levels in otherwise healthy overweight Japanese adults.Participants and Methods: Overall, 32 participants (23 males and 9 females) aged between 20 and 64 years with a BMI of 25 or more but less than 30 kg/m2 and a visceral fat area of 80 cm2 or more were included in this randomized double-blind clinical trial. The 20-week intervention involved two groups of participants -placebo group and ellagic acid (3.0 mg per day) group. The placebo or ellagic acid was taken daily with water 30 minutes before the main meal. At baseline (T0) and at 6 and 12 weeks, anthropometric measurements (body weight, BMI, body fat ratio, waist circumference, hip circumference), CT scans and blood triglyceride levels were measured. Results: Compared to the placebo, ellagic acid brought about statistically significant reductions in body fat ratio, triglycerides, body weight, BMI, waist circumference, hip circumference and visceral fat over the twelve-week trial period.Conclusion: The use of 3.0 mg ellagic acid daily for a 12-week period was effective in reducing body fat ratio and blood triglycerides as well as other anthropometric parameters, confirming the potential use of ellagic acid in the management of overweight patients. Keywords: Ellagic acid, Irvingia gabonensis, overweight, obesity, body fat, triglyceride, body weight, metabolic syndrome.